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      Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR.

      Nature genetics

      Base Sequence, Chromosome Mapping, DNA, genetics, Diabetes Mellitus, Type 1, HLA-DR4 Antigen, Haplotypes, Humans, Insulin, Molecular Sequence Data, Polymorphism, Genetic, Repetitive Sequences, Nucleic Acid

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          Abstract

          Recent studies have demonstrated that a locus at 11p15.5 confers susceptibility to insulin dependent diabetes mellitus (IDDM). This locus has been shown to lie within a 19 kb region. We present a detailed sequence comparison of the predominant haplotypes found in this region in a population of French Caucasian IDDM patients and controls. Identification of polymorphisms both associated and unassociated with IDDM has allowed us to define further the region of association to 4.1 kb. Ten polymorphisms within this region are in strong linkage disequilibrium with each other and extend across the insulin gene locus and the variable number tandem repeat (VNTR) situated immediately 5' to the insulin gene. These represent a set of candidate disease polymorphisms one or more of which may account for the susceptibility to IDDM.

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          Most cited references 30

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          Hypervariable ‘minisatellite’ regions in human DNA

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            Microsatellites for linkage analysis of genetic traits.

             C Hearne (1992)
            Microsatellites are tandem repeats of simple sequence that occur abundantly and at random throughout most eukaryotic genomes. Since they are usually less than 100 bp long and are embedded in DNA with unique sequence, they can be amplified in vitro using the polymerase chain reaction. Microsatellites are easy to clone and characterize and display considerable polymorphism due to variation in the number of repeat units. This polymorphism is sufficiently stable to use in genetic analyses. Microsatellites are therefore ideal markers for constructing high-resolution genetic maps in order to identify susceptibility loci involved in common genetic diseases.
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              Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility.

              A class of alleles at the VNTR (variable number of tandem repeat) locus in the 5' region of the insulin gene (INS) on chromosome 11p is associated with increased risk of insulin-dependent diabetes mellitus (IDDM), but family studies have failed to demonstrate linkage. INS is thought to contribute to IDDM susceptibility but this view has been difficult to reconcile with the lack of linkage evidence. We thus investigated polymorphisms of INS and neighbouring loci in random diabetics, IDDM multiplex families and controls. HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kilobase segment spanned by the 5' INS VNTR and the third intron of the gene for insulin-like growth factor II (IGF2). As INS is the major candidate gene from this region, diabetic and control sequence were compared to identify all INS polymorphisms that could contribute to disease susceptibility. In multiplex families the IDDM-associated alleles were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Our results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility which is located in a 19-kilobase region of INS-IGF2. Our results also suggest new ways to map susceptibility loci in other common diseases.
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                Author and article information

                Journal
                8358440
                10.1038/ng0793-305

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